Immune development in early life (IDEAL) shapes vaccine response, respiratory infectious diseaseand asthma

项目总结 到目前为止，定义和应用精确内切分型的努力仅限于成人研究。然而， 早期生命中的免疫发育(理想)是动态的，不同个体之间存在差异，这表明 与不同的病理生理机制相对应的内型将与年龄相关。我们建议 因此，我们将采用一种新的方法来研究定义明确的儿童纵向队列，并将其用于硅胶 结合特定年龄的人体体外模型对现有和预期收集的数据进行综合分析 识别将理想药物从疾病内型重定向至与之相关的药物的系统 健康。我们选择了三个临床终点与系统生物学数据相关联，以确定理想的 内型：a)疫苗反应性，因为疫苗是最重要的生物医学干预措施 减少儿童疾病；b)呼吸道感染，这是儿童最大的负担 传染病；和c)哮喘，一种免疫介导的呼吸系统疾病，表现为 儿童时期患病，并造成巨大的健康负担。这些端点中的每一个都展示了大量 个体间的可变性使强大的系统生物学工具能够提取有意义的相关性。我们 将协调和研究由儿童时期纵向队列组成的理想元队列(IMC) 在北美、非洲和澳大拉西亚注册。我们在纽约州罗切斯特的临床核心在全国范围内 在儿童免疫个体发育研究中表现突出。项目(公关)1将采用尖端、交叉 平台综合生物信息学工具，以确定与临床终点相关的内型。PR2，Will 将表观遗传分析工具应用于相同的样本，并转换为宿主免疫参数 硅胶衍生的签名。在PR3中，与内型相关的关键生物标志物和途径将在 在体外建立因果关系并确定影响因素(如蛋白质、代谢产物、佐剂、疫苗) 可能会将理想从不利的内型重定向到有利的内型。我们已经优化了 支持婴儿系统生物学的样本节省分析和我们发表的初步数据 证明可行性、稳健性、理想性，并根据临床情况提出不同的签名。我们的十字架- 平台验证和与临床表型相关的内源性类型的相关性将识别 可预测/可操作的生物标志物：I)系统/粘膜中理想的和微生物群的特征 分组(总体目标1)，二)识别内型特异性生物标记物(总体目标2)，在 将理想内型重新导向健康的体外干预措施(总体目标3)。整体来说，我们会加强 并加快发现预测和预防儿童疾病的新方法。

PROJECT SUMMARY To date, efforts to define and apply precision endotyping has been limited to studies of adults. However, immune development in early life (IDEAL) is dynamic and varies between individuals suggesting that endotypes corresponding to distinct pathophysiological mechanisms will be age-dependent. We propose therefore a novel approach in which we will study well-defined longitudinal childhood cohorts and use in silico integrative analyses of existing and prospectively collected data coupled with age-specific human in vitro model systems to identify agents that redirect IDEAL away from disease endotypes towards those associated with health. We have selected three clinical endpoints to correlate with systems biology data to identify IDEAL endotypes: a) vaccine responsiveness, as vaccines are the most important biomedical intervention to reduce childhood disease; b) respiratory infection which represents the greatest burden of childhood infectious disease; and c) asthma, an immune-mediated respiratory disease which manifests in childhood and results in substantial health burden. Each of these endpoints demonstrates substantial inter-individual variability enabling powerful systems biology tools to extract meaningful correlations. We will harmonize and study an IDEAL Meta-Cohort (IMC) comprised of longitudinal childhood cohorts enrolled in North America, Africa and Australasia. Our Clinical Core in Rochester, NY, is nationally prominent in the study of childhood immune ontogeny. Project (PR) 1 will employ cutting edge, cross- platform integrative bioinformatics tools to identify endotypes associated with clinical endpoints. PR2, will apply epigenetic analysis tools to the same samples and translate to host immune parameters the in silico-derived signatures. In PR3, key endotype-associated biomarkers and pathways will be dissected in vitro to establish cause and effect and identify agents (e.g., proteins, metabolites, adjuvants, vaccines) that may redirect IDEAL away from unfavorable endotypes and towards favorable ones. We have optimized sample-sparing assays to enable systems biology in infants and our published preliminary data demonstrate feasibility, robust IDEAL, and suggest distinct signatures by clinical status. Our cross- platform validation and correlation with endotypes correlating with clinical phenotypes will identify predictive/actionable biomarkers by i) characterizing IDEAL and microbiome in systemic/mucosal compartments (Overall Aim 1), ii) identifying endotype-specific biomarkers (Overall Aim 2), identifying in vitro interventions that re-direct IDEAL endotypes towards health (Overall Aim 3). Overall, we will enhance and accelerate discovery of new approaches to predict and prevent childhood disease.